Project Summary/Abstract Glioblastoma multiforme (GBM) is a dreadful cancer with a median survival of 14 months due to a lack of effective therapy. Checkpoint blockade immunotherapies have shown promising clinical outcomes for several cancers, and as such there are now many early stage clinical trials for GBM. Trials are designed for both newly diagnosed and recurrent GBMs and in both cases, checkpoint blockade is administered on the background of standard of care (SOC) therapy for GBM, which consists of surgical debulking, followed by fractionated radiation (XRT) with concomitant and adjuvant temozolomide (TMZ) alkylating chemotherapy. In addition, most patients are subjected to steroid use (dexamethasone-Dex)) to alleviate post surgery neurological symptomatic relief. There is a critical deficiency in our understanding on how XRT/TMZ and steroid exposure affect the tumor microenvironment (TME), specifically the immune cells component. Therefore there is a pressing need to understand how the efficacy of checkpoint immunotherapies is affected by XRT/TMZ/Dex and delineate a clinical strategy that will maximize treatment effectiveness. In addition, we demonstrate that the composition and activation status of GBM immune infiltrates is influenced by the driver genotype of the GBM cells. Our proposal will fill a knowledge gap regarding the type and activation status of the immune infiltrate vis--vis tumor driver genotypes. The central hypotheses of our proposal are: 1) the immune landscape of GBM is related to the type of driver mutations (genotype) of the tumor and 2) the SOC for GBM will affect its immune component and function, both of which will directly influence the efficacy of PD-1 and CTLA-4 checkpoint blockade immunotherapies. We need to delineate those effects and understand them in order to modify GBM management protocols to take full advantage of the power of immunotherapy. We propose to use EGFR- and PDGFR?-driven genetically engineered mouse models, which accurately recapitulate human GBM, to determine the effects of tumor genotype on the immunofauna, to unveil the consequences of SOC on immune function and to relate those findings to clinical practice. Our project will deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate human disease to inform the conduct of clinical trials and to mechanistically interpret their outcomes.